The World Health Organization estimates that by 2020, major depressive disorder (MDD) will be the most common cause of disability, worldwide. Although approximately 1 in 6 Americans will suffer from MDD during their lifetime, many patients with MDD go undiagnosed in primary care settings, and 20% are incorrectly diagnosed with MDD. Given the substantial medical, economic and social costs involved with MDD, there is tremendous need for a simple objective biomarker test to aid clinicians in accurately identifying MDD. No test currently exists that can accurately diagnose MDD and distinguish it from other psychiatric conditions. Further, clinical response to antidepressant therapy requires as much as two months. There is enormous need for a test that can predict response within a few days of the inception of treatment. The potential market for an accurate diagnostic test for MDD is estimated at $5-8B annually. Payers of medical services would cover the cost of such a diagnostic test because accurately identifying and treating MDD would reduce the high medical costs arising from medical service delivery to patients with untreated depression, as well as improving outcomes for patients with comorbid medical conditions such as diabetes or heart disease. Another market for an MDD diagnostic test is pharmaceutical companies. These companies have uniformly retreated from discovery efforts in mood disorders, in part due to large-scale failure of numerous clinical trials. Part of the reason for these failures is the enrollment of inappropriate patients. An objective test of MDD could address this concern by providing certainty about the appropriateness of recruited subjects. The Pax Neuroscience diagnostic biomarker G?s Sequestration Assay (GSA) indicates that MDD patients have a significantly greater proportion of G?s captured in lipid rafts compared to non-depressed controls and can accurately identify patients suffering from MDD. Pax used the same principles that underpin the GSA to develop a C6 glioma (G?s -GFP) FRAP assay which can reliably predict antidepressant efficacy. The proposed studies will convert that assay into high content screening (HCS) format, enabling an HCS campaign to find novel small molecules that target MDD. In addition we will develop a secondary screen using Neural Stem Cells, induced from fibroblasts of depressed subjects with known responses to antidepressants (SSRIs), to confirm the efficacy of the screen. This secondary screen can be modified to evaluate treatment efficacy in MDD patients. This is an exciting proposal that offers an underlying technology that can both find new drugs and develop personalized therapy for depression.